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Comparison of 2 Tenofovir Prodrugs: TAF (GS 7340) and TDF

Tenofovir alafenamide fumarate (TAF) is an investigational prodrug of tenofovir. You will recall that the current tenofovir product, tenofovir disoproxil fumarate (TDF), also is a prodrug; so why are we interested in a new prodrug? This largely has to do with efforts to decrease the toxicity associated with tenofovir.

Both TDF and TAF require conversion to the active drug tenofovir diphosphate (DP). TDF is converted initially to tenofovir in the blood, then tenofovir is taken up into cells. In lymphocytes, macrophages, and some other cells, it is phosphorylated to the DP form. TAF, however, is largely delivered as TAF to lymphocytes and macrophages, then metabolized intracellularly to tenofovir and phosphorylated to the active tenofovir DP. Thus, as demonstrated by earlier Phase I studies, plasma levels of tenofovir are much lower--in fact, 90% lower--with TAF (25 mg daily) than with TDF (300 mg daily), and tenofovir DP levels are much higher within lymphocytes. It is thought that lower systemic exposure to tenofovir will help avoid some of the renal and bone toxicities associated with tenofovir. (In addition, the lower mg dosage will facilitate coformulation.)

At CROI, results were presented from a Phase II comparison of TAF with TDF in initial therapy. One hundred seventy subjects were randomized 2:1 to receive either of 2 single-dose combination tablets: TAF (10 mg) with emtricitabine/elvitegravir/cobicistat or tenofovir/emtricitabine/elvitegravir/cobicistat (Stribild), along with a placebo of the other. At baseline, subjects' median HIV RNA was 4.56 log10 copies/mL, with >100,000 copies/mL in 17% and 28% of the 2 groups, respectively; the median CD4 count was approximately 390 cells/µL, and the median estimated glomerular filtration rate (eGFR) was 115 mL/min/1.73 m2.

At week 24, by intention-to-treat (snapshot) analysis, HIV suppression to <50 copies/mL was seen in 86.6% of the TAF group and in 89.7% of the TDF group, (95% confidence interval [CI]: -15.7, 5.9; p = .36; the study was not powered for noninferiority determinations).

Adverse events were roughly similar in type and frequency between the 2 groups, but discontinuations owing to adverse events were seen in 4 TAF recipients and none of the TDF recipients; of these, only 1 adverse event was suspected to be related to study drugs.

On pharmacokinetic analyses, mean plasma levels of tenofovir DP were lower in the TAF arm than in the TDF arm; for example, the AUC was roughly 10 times lower. In peripheral blood mononuclear cells (PBMCs), intracellular levels of tenofovir DP were more than 5-fold higher in the TAF group than in the TDF group.

Evaluations of renal function showed a smaller increase in creatinine (0.07 mg/dL vs 0.12 mg/dL) and a smaller decrease in eGFR (-4.9 mL/min/1.73 m2 vs -11.8 mL/min/1.73 m2) in the TAF arm compared with the TDF arm; both comparisons were statistically significant. In dual-energy X-ray absorptiometry (DEXA) measures of bone mineral density, smaller decreases at both the spine (-0.8% vs -2.5%) and hip (-0.3% vs -2.0%) were seen in the TAF arm; again, both comparisons were statistically significant.

Clinical Bottom Line

The findings that TAF appears similarly effective as TDF in virologic suppression but potentially less toxic to kidneys and bone, if borne out in larger and longer studies, could be very important, given the many years of ART exposure that most patients will accumulate over their lifetime.

Studies also will be needed to evaluate the efficacy of TAF against hepatitis B, in persons with HIV/hepatitis B coinfection--to date there are no clinical data (and subjects with hepatitis B were excluded from the study discussed here).

TAF is undergoing further investigation, including in various coformulated pills (2 Phase III studies are examining the emtricitabine/elvitegravir/cobicistat formulation studied here, and other trials are looking at different combinations).